CN113636984B - Morpholine group-containing 1,3, 4-oxadiazole compound and preparation method and application thereof - Google Patents
Morpholine group-containing 1,3, 4-oxadiazole compound and preparation method and application thereof Download PDFInfo
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- CN113636984B CN113636984B CN202110951977.1A CN202110951977A CN113636984B CN 113636984 B CN113636984 B CN 113636984B CN 202110951977 A CN202110951977 A CN 202110951977A CN 113636984 B CN113636984 B CN 113636984B
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- -1 1,3, 4-oxadiazole compound Chemical class 0.000 title claims abstract description 25
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 9
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- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 claims abstract description 7
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- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- BVJOXYJFOYNQRB-UHFFFAOYSA-N morpholine;hydrobromide Chemical compound Br.C1COCCN1 BVJOXYJFOYNQRB-UHFFFAOYSA-N 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229950009846 scopolamine butylbromide Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application relates to a morpholine group-containing 1,3, 4-oxadiazole compound, a preparation method and application thereof. The compound has a structure shown in a general formula (I):
Description
Technical Field
The application relates to the technical field of pharmaceutical chemistry, in particular to a morpholine group-containing 1,3, 4-oxadiazole compound, and a preparation method and application thereof.
Background
Plant pathogens are a group of invasive microorganisms and are widely distributed worldwide, can invade various plants for nutritional competition and self-propagation, and cause serious diseases to important crops, severely threatening the quality and yield of agricultural products. For example, gibberella wheat (Gibberella saubinetii) is a filamentous ascomycete, a disease occurring on wheat caused by infection with various fusarium species. The germ can cause wheat seedling rot, stem basal rot, stalk rot and spike rot, and brings at least 10-20% yield reduction to the country where the wheat is planted each year. In addition, rice bacterial leaf blight bacteria (Xanthomonas oryzae) are rod-shaped gram-negative bacteria which can wither and whiten rice leaves, and bring about at least 10-50% yield reduction per year in countries where rice is planted. Citrus canker (Xanthomonas axonopodis pv. Citri) causes citrus decay, affecting citrus yield worldwide. Currently, in agricultural production, plant pathogens develop a degree of resistance to traditional fungicides due to their long-term abuse. Therefore, the novel efficient, low-toxicity and safe green pesticide is very significant.
Quaternary ammonium compounds have been particularly paid attention to the development of bactericides because they have various biological activities, particularly excellent bactericidal activity against bacteria and fungi. Morpholine salts as a member of the quaternary ammonium family have been reported in the literature to exhibit a broad spectrum of biological activity, such as; antibacterial, insecticidal, plant growth regulating, antitumor, antiinflammatory, etc. In our previous work, we developed and evaluated the antibacterial function of a series of pyridinium custom compounds, which were found to have excellent antibacterial activity, but higher phytotoxicity to rice leaves.
In order to develop a safe quaternary ammonium compound which can be applied to agriculture for preventing and controlling plant bacterial diseases, a morpholine bracket is adopted to replace a pyridyl group with a planar structure, a compound containing 1,3, 4-oxadiazole groups is prepared, the biological activity of the compound is tested, and an important scientific basis is provided for the research and development and the creation of new pesticides.
The biological activity of morpholino compounds was studied as follows:
wang et al 2017 [ Wang, x.l.; zhou, j.n.; li, R; pan, x.l.; ren, h.y.; jun, l.improvement of Quality of Nonanesthetic Colonoscopy by Preoperative Admini stration of Pinaverium Bromide [ J ]. Chinese Medical Journal,2017, 130:631-635 discusses the effects of the prophylactic administration of the morpholinium medical drug, pinaverium bromide, prior to colonoscopy, at various time points alone or in combination with scopolamine butyl bromide.
Bakhite et al 2014 [ Bakhite, E.A.; abd-Ella, a.a.; el-protected, m.e.a.; abdel-Raheel, S.A.A.Pyridine Derivatives as instruments.Part 1: synthesis and Toxicity of Some Pyridine Derivatives Against Cowpea Aphid, aphis craccivora Koch (Homoptera: aphididae) [ J ]. J.Agric.food Chem,2014, 62, 9982-9986] the insecticidal activity of a series of compounds was measured, and the bioassay results showed that the insecticidal activity of Compound 1 containing a morpholinium salt structure was about 4 times that of acetamiprid insecticide.
2016 Yang et al [ Yang, s.c.; aljuffali, i.; sung, c.t.; lin, C.F.; fang, j.y.Antimicobidi activity of topically-applied soyaethyl morpholinium ethosulfate micelles against Staphylococcus species [ J ]. Nanomedicine,2016, 11 (6): 657-671] the antimicrobial efficacy of soy ethylmorpholine on staphylococcus aureus and methicillin-resistant staphylococcus aureus (MRSA) ethylsulfate (SME) was evaluated. The results show that the minimum inhibitory concentration and the minimum bactericidal concentration of the soybean ethylmorpholine on staphylococcus aureus and MRSA are respectively 1.71-3.42 and 1.71-6.84 micrograms/milliliter, and the soybean ethylmorpholine has low cytotoxicity on mammals.
Disclosure of Invention
One of the purposes of the present application is to provide a morpholine group-containing 1,3, 4-oxadiazole compound or a stereoisomer thereof, or a salt or solvate thereof.
It is another object of the present application to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, and a method for preparing the same.
It is still another object of the present application to provide a composition comprising the above compound or a stereoisomer thereof, or a salt thereof or a solvate thereof.
It is a further object of the present application to provide the use of the above compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, or the composition.
It is another object of the present application to provide a method for controlling agricultural pests using the above-mentioned compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, or the composition.
In order to achieve the above purpose, the present application adopts the following technical scheme:
a morpholine group-containing 1,3, 4-oxadiazole compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, the compound having a structure as shown in the general formula (I):
r is independently selected from one or more of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted α -methyl-benzyl, optionally substituted or unsubstituted benzenesulfonyl; x is an oxygen atom or a sulfur atom; n is n 1 0,1,2 or 3; n2 is a natural number greater than 1, preferably n is 1 to 20, more preferably n is 2 to 18, and more preferably n is 2 to 15.
Preferably, R is selected from hydrogen, methyl, ethyl, hexyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl;
most preferably, the morpholine group-containing 1,3, 4-oxadiazole compound is selected from the following compounds:
the application also provides an intermediate compound:
the application also provides a preparation method of the morpholine group-containing 1,3, 4-oxadiazole compound, which comprises the following steps:
preferably, the method further comprises the steps of:
most preferably, the method further comprises the steps of:
wherein R is selected from one or more of hydrogen, optionally substituted or unsubstituted alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted α -methyl-benzyl, optionally substituted or unsubstituted benzenesulfonyl; x is an oxygen atom or a sulfur atom; n is n 1 0,1,2 or 3; n is a natural number greater than 1.
The application also provides a composition containing the compound or a stereoisomer thereof, or a salt or a solvate thereof, and an agriculturally useful adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from the group consisting of Emulsifiable Concentrates (EC), powders (DP), wettable Powders (WP), granules (GR), aqueous Solutions (AS), suspensions (SC), ultra low volume sprays (ULV), soluble Powders (SP), microcapsules (MC), smoke agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
The compound or the stereoisomer, the salt or the solvate thereof or the composition can be used for preventing and controlling agricultural diseases and insect pests, preferably, the agricultural diseases and insect pests are plant bacterial diseases or fungal diseases; more preferably, the agricultural pest is a plant leaf blight and a plant canker; most preferably, the agricultural pest is rice bacterial leaf blight, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi fruit canker, apple canker, cucumber gray mold pathogen, pepper fusarium wilt pathogen, rape sclerotinia rot, wheat red mold pathogen, potato late blight pathogen.
The application also provides a method for preventing and controlling agricultural diseases and insect pests, which enables the compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition to act on harmful substances or living environments thereof; preferably, the agricultural pest is a bacterial or fungal plant disease; more preferably, the agricultural pest is rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwifruit canker, apple canker, cucumber gray mold, pepper fusarium wilt pathogen, rape sclerotinia rot, wheat red mold pathogen, potato late blight pathogen.
The present application also provides a method for protecting plants from agricultural pests comprising the method step wherein the plants are contacted with said compound or stereoisomer thereof, or a salt thereof or a solvate thereof, or said composition.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. For example "C 1-10 Alkyl "(or alkylene) is intended to mean C1, C2, C3, C4, C5, C6,C7, C8, C9 and C10 alkyl groups. In addition, e.g. "C 1-6 Alkyl "means an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms is replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like.
"alkenyl" is a hydrocarbon that includes both straight or branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. For example "C 2-6 Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.
The term "substituted" as used herein refers to any one or more hydrogen atoms on a specified atom or group being replaced with a selected specified group, provided that the specified atom's general valency is not exceeded. Substituents are named to the central structure, unless otherwise indicated. For example, it is understood that when (cycloalkyl) alkyl is the possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., c= C, C =n or n=n). When referring to substitution, particularly polysubstituted, it is meant that a plurality of substituents are substituted at various positions on the indicated group, such as dichlorobenzyl refers to 2, 3-dichlorobenzyl, 2, 4-dichlorobenzyl, 2, 5-dichlorobenzyl, 2, 6-dichlorobenzyl, 3, 4-dichlorobenzyl and 3, 5-dichlorobenzyl.
Combinations of substituents and variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. The stable compound or stable structure implies that the compound is sufficiently stable when isolated from the reaction mixture in useful purity, and is formulated to form an effective therapeutic agent.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-or 6-membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14-membered tricyclic groups, having at least one heteroatom (O, S or N) in at least one ring, said heteroatom-containing ring preferably having 1,2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and/or from 1 to 4 nitrogen atoms provided that the total number of heteroatoms in each ring is 4 or less and that each ring has at least one carbon atom. The fused ring completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen may optionally be oxidized and quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one wholly aromatic ring and the nitrogen other fused rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring.
The compounds of the present application are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from inorganic and/or organic acids and bases. In addition, the term "salt" may include zwitterionic (inner salts), such as when the compounds of formula I contain basic moieties such as amine or pyridine or imidazole rings, and acidic moieties such as carboxylic acids. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or bioactivity of the salt. However, other salts may be useful, such as by employing isolation or purification steps in the preparation process, and are therefore also included within the scope of the present application.
Preferably C 1 -C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c (C) 2 -C 5 Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.
When referring to substituents as alkenyl, alkyl, aryl, benzyl, cycloalkyl, or when these substituents are specifically a particular alkenyl, alkyl, aryl, benzyl, cycloalkyl, one to three of the above substituents are meant. For example chlorobenzyl refers to one to three chloro-substituted benzyl groups.
By adopting the technical scheme, the application synthesizes a series of 1,3, 4-oxadiazole compounds containing morpholine groups by taking 5-phenyl-1, 3, 4-oxadiazole-2-thiol as a starting material, and discovers that the compounds have good inhibition effect on pathogenic plant bacteria, and have good inhibition effects on pathogenic bacteria [ such as bacterial blight of paddy (Xanthomonas oryzae pv. Oryzae, xoo) and citrus canker (Xanthomonas axonopodis pv. Citri, xac), thus providing important scientific basis for research, development and creation of new pesticides.
Drawings
Fig. 1 is a phytotoxicity profile (7 days of treatment) after incubation with different concentrations of compound 12: (a) 0 μg/mL, (b) 200 μg/mL.
Examples
The application is further illustrated by the following examples. It should be understood that the methods described in the examples of the present application are only for illustrating the present application, and not for limiting the present application, and that simple modifications to the preparation methods of the present application under the concept of the present application are within the scope of the present application as claimed. All the starting materials and solvents used in the examples were commercially available products of the corresponding purity.
Example 1: preparation of intermediate 2- ((8-bromooctyl) mercaptan) -5-phenyl-1, 3, 4-oxadiazole
5-phenyl-1, 3, 4-oxadiazole-2-thiol (1 mmol), K 2 CO 3 (1.3 mmol) and 8mL of DMF were added to a 25mL round bottom flask, then 1, 8-dibromooctane (1.3 mmol) was added and the reaction was terminated after stirring at room temperature for 2 hours. Desolventizing, column chromatography (eluent petroleum ether (ethyl acetate=10) (1, V/V)) gives intermediates. Meanwhile, experimental procedures and feeding ratios of other chain length intermediates were identical to those of example 1 except that 1, 8-dibromooctane was changed to a different chain length.
Example 2: 4-methyl-4- (8- ((5-phenyl-2-1, 3, 4-oxadiazolyl) thiol) octyl) morpholin-4-ium bromide
2- ((8-bromooctyl) mercaptan) -5-phenyl-1, 3, 4-oxadiazole (0.4 mmol) and 4-methylmorpholine (4).55 mmol) in 4mL CH 3 CN was added to a 15mL reaction flask, and the mixture was refluxed at 85℃for 8 hours. TLC followed the reaction completion. Water (3X 20 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was treated with anhydrous Na 2 SO 4 Drying, suction filtering, and concentrating under reduced pressure. The crude residue was further purified by silica gel column chromatography using CH 2 Cl 2 And CH (CH) 3 OH (20:1, V/V) was used as eluent to give a pale yellow solid in 63.2% yield, and the remaining experimental procedures and proportions of the feeds were consistent with example 2.
The remaining morpholine group-containing 1,3, 4-oxadiazoles were synthesized using the corresponding starting materials or substituents, with reference to the procedure of examples 1 and 2.
Nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the compounds of Table 1
Physical and chemical Properties of the Compounds of Table 2
Pharmacological example 1:
EC 50 (median effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to a compound, and is also an important parameter for setting the concentration of the compound when researching the action mechanism of the target compound. In the concentration gradient experiment, proper 5 concentrations are set by adopting a double dilution method, and finally the inhibition rate of the medicament to plant pathogenic bacteria and the medicament concentration are converted into logarithmic values, and the virulence curve is obtained by SPSS software regression analysis, so that EC is calculated 50 。
Testing the effective medium concentration EC of the target compound to plant pathogenic bacteria by using turbidity method 50 The test subjects were rice bacterial leaf blight bacteria (Xoo) and citrus canker bacteria (Xac). DMSO was dissolved in the medium as a blank. Putting rice bacterial leaf blight bacteria (rice bacterial leaf blight pathogenic bacteria are in an M210 solid culture medium) into an NB culture medium, and carrying out shake culture in a constant-temperature shaking table at 28 ℃ and 180rpm until the bacterial leaf blight bacteria are in a logarithmic growth phase for later use; the citrus canker fungus (on M210 solid medium) is placed in NB medium and shake-cultured in a thermostatic shaker at 28℃and 180rpm until logarithmic growth phase is ready for use. 5mL of toxic NB liquid medium with different concentrations (for example, 100, 50, 25 and 12.5,6.25 mug/mL) of the medicament (compound) is added into a test tube, 40 mu L of NB liquid medium containing phytopathogenic bacteria is respectively added, and the culture is carried out by shaking in a constant-temperature shaking table at 28 ℃ and 180rpm, so that the rice bacterial leaf blight pathogenic bacteria are cultured for 36h and the citrus canker bacteria are cultured for 48h. Measuring OD of bacterial solutions with various concentrations on a spectrophotometer 595 Values, and additionally determining the OD of corresponding concentrations of toxic sterile NB liquid medium 595 Values.
Corrected OD = bacteria-containing medium OD-sterile medium OD
Inhibition ratio = [ (corrected control culture medium bacterial liquid OD value-corrected toxic culture medium OD value)/corrected control culture medium bacterial liquid OD value ] ×100
The present application is described with the aid of examples, but the contents of examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
EC of the compounds of table 3 against phytopathogenic bacteria 50
As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria (such as Rhizoctonia solani. Of rice) in an in vitro test. From the analysis of the structure and activity, it can be seen that the antibacterial activity of all the compounds is obviously improved along with the extension of the carbon chain. For example, EC of all compounds containing 10 or 12 carbon chains in the structure against bacterial leaf blight bacteria and citrus canker bacteria of rice 50 Are all within 10, and the 7 compounds with the numbers of 3, 6, 8, 9, 12, 15 and 18 have extremely excellent activity on rice bacterial blight bacteria, and EC 50 1.70, 1.69, 1.90, 1.80, 2.8, 1.40 and 1.78 μg/mL, respectively; the 6 compounds with the numbers of 3, 6, 9, 12, 15 and 18 show extremely obvious activity on citrus canker, and EC 50 1.61, 2.89, 1.61, 0.90, 1.45 and 1.69. Mu.g/mL, respectively. Meanwhile, most of the compounds have excellent antibacterial activity and the minimum EC of the rice paraquat resistant compared with the control medicines (the metconazole and the thiabendazole) 50 1.40 mug/mL, compared with the thiabendazole serving as a control drug, the activity is improved by 48 times; minimum EC against citrus canker pathogens 50 The activity is improved by 105 times compared with the control drug of the metconazole at 0.90 mug/mL. Therefore, the compound has great research prospect and can be used for preparing pesticides against plant pathogenic bacteria.
Pharmacological example 2:
shows the best activity (EC) on rice bacterial leaf blight bacteria based on compound 12 50 1.40. Mu.g/mL) of compound 12 was used for a toxicity potting experiment for rice bacterial leaf blight. The specific experimental steps are as follows:
preparing a 200 mug/mL drug-containing solution of the compound 12 by using a Tween20 solution with concentration less than 1%; spraying the prepared liquid medicine on the surfaces of rice leaves which have grown for 4 weeks respectively until liquid drops drop down; equivalent DMSO controls without agent were set, three replicates for each treatment, and toxicity was checked after 7 days.
The embodiment of the application is assisted by the technical scheme of the application, but the content of the embodiment is not limited to the embodiment, and the experimental result of the target compound is shown in the attached figure 1.
As can be seen from fig. 1, in the toxicity test, the toxicity of the compound 12 with the concentration of 200 μg/mL to rice leaves is basically consistent with that of a blank control group, and the compound is basically nontoxic, which indicates that the 1,3, 4-oxadiazole compound containing morpholine groups has better biological friendliness, reduces the phytotoxicity of high-activity salt compounds, and has a certain research prospect.
Pharmacological example 3:
shows the best activity (EC) on rice bacterial leaf blight bacteria based on compound 12 50 1.40. Mu.g/mL) of the compound 12 was used for the in vivo potting experiment of bacterial leaf blight of rice. The specific experimental steps are as follows:
protective activity: compound 12, a control drug, namely buprofezin (20% content preparation) is prepared into 200 mug/mL drug-containing solution by using less than 1% Tween20 solution, and two more compound 12 solutions with the concentration of 200 mug/mL are prepared; spraying the prepared liquid medicine on the surfaces of rice leaves which have grown for 8 weeks respectively until liquid drops drop down; after 24 hours, the blade is stained with OD at a distance of 2cm from the tip 595 Scissors of rice bacterial leaf blight bacteria in the range of 0.6-0.8 cut off leaf tips, and the wounds are immersed in bacterial liquid for about 10s, equal amounts of DMSO and bacterial leaf control without medicines are arranged, each treatment is repeated three times, disease conditions are checked after 14 days, the disease spot length and total length of rice leaves are recorded, and disease indexes and prevention effects are calculated.
The leaf area was calculated by first measuring the spot area of each leaf and the total leaf area, and then measuring the percentage of the total spot area. Second, the leaves were classified according to the following ranking criteria: grade 1, the area of lesions is less than 5% of the total leaf area. Stage 3, the area of the lesion accounts for 6-10% of the total leaf area; stage 5, the area of the lesion is 11-20% of the area of the whole leaf; 7, the area of the lesion accounts for 21-50% of the area of the whole leaf; stage 9, the area of the disease spots accounts for more than 50% of the area of the whole blade; the method for calculating the disease index is as follows:
disease index = Σ (number of leaves per grade x corresponding grade)/(total number of leaves x highest grade)
The control effect calculation method comprises the following steps:
control% = (control disease index-treatment disease index)/control disease index x 100%
Therapeutic activity: the blade is 2cm away from the tip of the blade and is stained with OD 595 Scissors of rice bacterial leaf blight bacteria in the range of 0.6-0.8 cut off leaf tips, and the wounds are immersed in bacterial liquid for about 10 s; after 24 hours, the prepared liquid medicine and the liquid medicine added with the auxiliary agent are sprayed on the surface of the rice leaf which has grown for 8 weeks respectively until liquid drops drop, equal amounts of DMSO and fungus leaf contrast without the agent are arranged, each treatment is repeated three times, the disease condition is checked after 14 days, the disease spot length and the total length of the rice leaf are recorded, the disease index and the prevention effect are calculated, and the calculation method is the same.
The present application is described with the aid of examples, but the contents of examples are not limited thereto, and the experimental results of the target compounds are shown in table 4.
Table 4 protection and therapeutic Activity of Compound 12 against bacterial leaf blight of Rice
As can be seen from table 4, compound 12 showed good therapeutic activity (55.95%) and protective activity (53.09%) against rice bacterial blight bacteria in vivo experiments. Is superior to the control drug of the buprofezin (37.53 percent of therapeutic activity and 36.68 percent of protective activity). Thus, the compounds are extremely promising in research.
Pharmacological example 4:
the antibacterial activity of the compound against plant pathogenic fungi such as pepper fusarium wilt (Fusarium oxysporum, f.o.), blueberry root rot (Phytophthora cinnamomi, p.c.) and the like is measured on a PDA culture medium by adopting a mycelium growth rate inhibition method, and the strains are activated in advance. Weighing a compound to be measured by a ten-thousandth balance, adding 1mL of DMSO to dissolve the compound, transferring the compound to a 15m L sterilized centrifuge tube in a sterile operation table, adding 9mL of Tween-20 to dissolve 10mL of the compound, pouring the compound into a culture medium, uniformly mixing, and then evenly split charging the compound into 9 culture dishes for later use; in a sterile operation table, a bacterial colony growing normally is made into a bacterial cake by a sterile puncher (5 mm), the bacterial cake is reversely buckled in the center of a culture medium by a bacterial inoculating ring, the bacterial cake is cultured for 3 to 5 days at the temperature of 28 ℃, when a control bacterial colony grows to 2/3 of the diameter of the whole flat plate, the bacterial colony is measured for 2 times by a straight ruler according to a cross method, and the diameter of the bacterial colony is calculated by an average value. In the initial stage, 25 mug/m L is selected as a preliminary screening concentration, and the compound is subjected to an EC50 test when the corresponding germ inhibition rate is greater than 50% at the preliminary screening concentration, and the hypha growth inhibition rate is determined according to the following formula. Hymexazol was included as a control agent in the test.
The calculation formula is as follows:
inhibition (%) = (C1-C) 2 )/(C 1 -0.4) x 100 formula:
C 1 control colony diameter, i.e. DMSO-treated colony diameter;
C 2 the diameter of the treated colony, namely the diameter of the colony treated by adding the medicine;
0.5-is the diameter of the parent fungus cake.
The present application is described with the aid of examples, but the contents of examples are not limited thereto, and some experimental results of target compounds are shown in table 5.
Inhibition of phytopathogenic fungi by the compounds of Table 5 (25. Mu.g/mL)
As can be seen from Table 5, in the in vitro test, a part of the target compounds showed good inhibitory activity against plant pathogenic bacteria (such as pepper fusarium wilt and blueberry root rot) at 25.0 μg/mL. Wherein, the inhibition rate of the compounds 2,3, 6, 8, 9 and 15 to pepper fusarium wilt is 43.45-59.52 percent, which is superior to that of the contrast medicine hymexazol (39.22 percent). For the blueberry root rot fungus,
the inhibition of compounds 5 and 6 was 50.16% and 44.98%, respectively. This result shows that the compounds of the present application can also be used as antifungal leads for the design of new bactericides in the future.
Claims (4)
1. A morpholine group-containing 1,3, 4-oxadiazole compound or a salt thereof, characterized by being selected from the following compounds:
2. a composition comprising a compound of claim 1 or a salt thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide, or herbicide; the formulation of the composition is selected from emulsifiable concentrates, powders, granules, water agents, suspending agents, ultra-low volume sprays, micro-capsules, smoke agents and aqueous emulsion.
3. Use of a compound of claim 1 or a salt thereof, or a composition of claim 2, for controlling agricultural pests, which are bacterial blight of rice, canker of citrus, pepper wilt pathogen, blueberry root rot pathogen.
4. A method for controlling agricultural plant diseases and insect pests, which is characterized by comprising the following steps: allowing the compound according to claim 1 or a salt thereof, or the composition according to claim 2 to act on a pest or its living environment; the harmful substances are rice bacterial leaf blight germs, citrus canker germs, pepper fusarium wilt germs and blueberry root rot germs.
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